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CROI 2014: Early Treatment Reduces Viral Reservoirs but Does Not Prevent Rebound

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Antiretroviral therapy started during the first several days after infection limited dissemination of an HIV-like virus throughout the body and establishment of cellular and tissue reservoirs in monkeys, though it did not prevent the virus from coming back after stopping treatment, according to research presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2014) last week in Boston.

Afam Okoye and colleagues from the Vaccine and Gene Therapy Institute in Florida and the Oregon Health and Science University looked at the effect of early treatment on viral reservoirs in rhesus macaque monkeys infected with SIV -- a primate virus similar to HIV -- when antiretroviral therapy (ART) is started either prior to peak viral replication, at or near the time of peak viral replication, or during early chronic infection.

From the very earliest stages of infection, HIV replicates and "seeds" itself in cellular reservoirs including long-lived memory T-cells as well as anatomical reservoirs such as the brain and gut. As part of the research towards a cure for HIV, researchers have explored whether antiretroviral therapy started very soon after infection can limit this process.

A group of French patients known as the VISCONTI Cohort appear to be controlling HIV on their own after interrupting ART that was started during very early infection, and a baby started on treatment within about 30 hours after birth shows no signs of ongoing infection despite being off ART for 2 years.

These and other cases suggest that reservoirs established early during acute infection -- prior to peak viral replication -- "may be quantitatively and qualitatively different from those established later in chronic infection and perhaps be more amenable to cure," the researchers noted as background.

Previous research in monkeys indicated that the size of the SIV reservoir in peripheral blood mononuclear cells (PBMCs) and tissues increases significantly between day 7 and day 10 after infection, and that the viral reservoir seeded during early acute infection is largely made up of CD4 memory T-cells, including central, transitional, and effector memory cells.

In this study, monkeys were started on multidrug therapy at day 7 (n=2), day 10 (n=2), or day 42 (n=18) after being intravenously exposed to SIV. ART consisted of tenofovir and emtricitabine (the drugs in Truvada), the integrase inhibitor dolutegravir (Tivicay), and ritonavir-boosted darunavir (Prezista).

The researchers measured SIV viral load in blood plasma, cell-associated virus in PBMCs, and SIV in bone marrow, small intestine mucosa or gut tissue, and lymph node biopsy samples using real-time quantitative PCR at various time points.

Results

  • ART initiation prior to peak virus replication led to lower peak plasma viral load and earlier viral suppression.
  • In the 2 monkeys treated from day 7, plasma viral load continued to rise after ART initiation, peaked by day 12, then declined to undetectable (<30 copies/mL) after 6 weeks on ART.
  • In the 2 macaques started on treatment at day 10, plasma viral load peaked on day 12 and did not become undetectable until 18 weeks on ART.
  • Among the 18 monkeys treated later, plasma viral load peaked between 12 and 14 days, and some animals did not achieve complete viral suppression even after 32 weeks on ART.
  • SIV DNA levels in PBMCs and tissues increased exponentially between 7 to 10 days after infection.
  • Early ART decreased levels of SIV DNA in circulating lymphocytesand virus levels in all tested tissues.
  • After 32 weeks, mean SIV DNA levels in PBMCs were 2.5 log for those started on ART at day 7, 3.5 log for those started at day 10, and 4.4 log for those started at day 42.
  • There was a significant correlation between peak plasma viral load and levels of SIV DNA in PBMCs at 32 weeks after infection.
  • In all tissues, there was greater increase in virus levels by delaying treatment from day 7 to day 10, than there was from day 10 to day 42.
  • Replication competent virus was undetectable by co-culture in all monkeys started on ART at day 7 or day 10, but detected in all those started at day 42.
  • However, even in monkeys treated early, viral rebound occurred soon after stopping ART at week 32, indicating that replication-competent virus is still present.
  • In addition, transferring lymph nodes from infected monkeys treated at day 7 to treatment-naive animals resulted in productive infection, again showing that infectious virus is present.

"Early ART, when initiated prior to peak virus replication, limits systemic virus dissemination and seeding of the reservoir in peripheral and extra-lymphoid mucosal compartments," the researchers concluded.

"A delay as short as 3 days during the 'hyperacute' phase can result in 1-2 logs higher tissue-based reservoir size, once therapy is started and maintained," they continued. "Reservoirs established during acute infection are capable of inducing rapid viremia in naive animals and viral rebound following ART cessation."

"Aggressive monitoring for acute infection with immediate introduction of ART could profoundly influence treatment outcomes and enhance viral eradication strategies," they suggested.

Speaking from the audience, Deborah Persaud from Johns Hopkins -- who at last year's CROI first reported on the apparently functionally cured Mississippi baby and this year described another baby in Long Beach who also appears free of HIV, though this child remains on ART -- suggested that 7 days is perhaps already too late. "This is relevant to perinatal infection, to not just minimize but block establishment of reservoirs," she said.

At a press conference following his presentation, Okoye acknowledged that to achieve the best results, "we may have to treat within 36 hours."

3/14/14

Reference

AA Okoye, M Rohankhedkar, M Reyes, et al. Early Treatment in Acute SIV Infection Limits the Size and Distribution of the Viral Reservoir. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6. Abstract 136LB.